Site-specific conjugation of linker drugs to antibodies and resulting ADCS

Abstract

The present invention relates to antibody-drug conjugates (ADCs) wherein a linker drug is site-specifically conjugated to an antibody through an engineered cysteine, and their use as a medicament, notably for the treatment of human solid tumours and haematological malignancies, in particular breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, prostate cancer, and leukaemia.

The invention claimed is: 
     
       1. A method of treating human solid tumors or haematological malignancies in a patient in need thereof, comprising administering to said patient an effective amount of an antibody-drug conjugate compound (ADC);
 wherein said ADC comprises an antibody or antigen binding fragment thereof, having an engineered cysteine at heavy chain position 41 (according to Kabat numbering) and a linker drug conjugated to said antibody or antigen binding fragment through said engineered cysteine wherein said antibody binds to an antigen target that is expressed on the cell surface of said tumor or malignancy. 
 
     
     
       2. The method according to  claim 1 , wherein said patient has a solid tumor selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, urothelial cancer, ovarian cancer, uterine cancer, lung cancer, mesothelioma, liver cancer, pancreatic cancer, and prostate cancer. 
     
     
       3. The method according to  claim 1 , wherein said patient has a haematological malignancy, wherein the haematological malignancy is leukaemia. 
     
     
       4. The method according to  claim 1 , wherein the antibody or antigen binding fragment of said ADC further comprises an engineered cysteine at position 375 of the heavy chain (according to Eu numbering) and linker drug is conjugated through said engineered cysteine at position 375. 
     
     
       5. The method according to  claim 1 , wherein said linker drug comprises a cytotoxic drug selected from the group consisting of anthracyclines, duocarmycins, pyrrolobenzodiazepine (PBD) dimers, calicheamicins, maytansinoids, and auristatins. 
     
     
       6. The method according to  claim 5 , wherein said cytotoxic drug is monomethyl auristatin E (MMAE) or emtansine (DM1). 
     
     
       7. The method according to  claim 5 , wherein said cytotoxic drug is a duocarmycin derivative. 
     
     
       8. The method according to  claim 7 , wherein said ADC has the formula (I) 
       
         
           
           
               
               
           
         
         wherein said Antibody is the antibody or antigen binding fragment thereof that contains the engineered cysteine at heavy chain position 41, 
         n is 0, 1, 2, or 3, 
         m represents an average DAR of from 1 to 6, 
         R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         y is 1-16, and 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
       9. The method according to  claim 8 , wherein
 n is 0 or 1, 
 m represents an average DAR of from 1.5 to 2, 
 R 1  is 
 
       
         
           
           
               
               
           
         
         y is 1-4, and 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
       10. The method according to  claim 9 , wherein said ADC has the formula (II) 
       
         
           
           
               
               
           
         
       
     
     
       11. The method according to  claim 1 , wherein said patient has a solid tumor selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, ovarian cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), and malignant pleural mesothelioma; and
 wherein said antibody of said ADC is an anti-5T4 monoclonal antibody. 
 
     
     
       12. The method according to  claim 11 , wherein said anti-5T4 monoclonal antibody has a heavy chain that comprises the amino acid sequence of SEQ ID NO:8 and a light chain that comprises the amino acid sequence of SEQ ID NO:11. 
     
     
       13. The method according to  claim 11 , wherein said ADC has the formula (I) 
       
         
           
           
               
               
           
         
         wherein said Antibody is the anti-5T4 monoclonal antibody that contains the engineered cysteine at heavy chain position 41, 
         n is 0, 1, 2, or 3, 
         m represents an average DAR of from 1 to 6, 
         R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         y is 1-16, and 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
       14. The method according to  claim 13 , wherein said ADC has the formula (II) 
       
         
           
           
               
               
           
         
       
     
     
       15. The method according to  claim 13 , which further comprises administering to said patient an effective amount of one or more of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof. 
     
     
       16. The method according to  claim 1 , wherein said patient has a solid tumor, wherein the solid tumor is prostate cancer; and
 wherein said antibody of said ADC is an anti-PSMA monoclonal antibody. 
 
     
     
       17. The method according to  claim 16 , wherein said anti-PSMA monoclonal antibody has a heavy chain that comprises the amino acid sequence of SEQ ID NO:2 and a light chain that comprises the amino acid sequence of SEQ ID NO:5. 
     
     
       18. The method according to  claim 16 , wherein said ADC has the formula (I) 
       
         
           
           
               
               
           
         
         wherein said Antibody is the anti-PSMA monoclonal antibody that contains the engineered cysteine at heavy chain position 41, 
         n is 0, 1, 2, or 3, 
         m represents an average DAR of from 1 to 6, 
         R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         y is 1-16, and 
         R 2  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
       19. The method according to  claim 18 , wherein said ADC has the formula (II) 
       
         
           
           
               
               
           
         
       
     
     
       20. The method according to  claim 18 , which further comprises administering to said patient an effective amount of one or more of a therapeutic antibody or a chemotherapeutic agent, or a combination thereof.